Project Summary Establishing and maintaining a postmitotic state is essential for normal development and organ function. Cells that fail to exit, or reenter, the cell cycle commonly die or continue proliferating unchecked. Despite the importance of these processes the mechanisms that drive cells into, and maintain them in, a non-proliferative state are incompletely understood. The long-term goal of this research is to identify the mechanisms that control these processes in the mammalian retina. The objectives of this application are to characterize a new molecule we have identified that is implicated in maintaining postmitotic retinal cells in a non-proliferative state. Our preliminary data support a central hypothesis that Maturin, regulates postnatal retinogenesis, and Maturin loss is sufficient for differentiated retinal cells to reenter the cell cycle and generate additional retina. The rationale for the proposed experiments is that that they will distinguish between two distinct models. Maturin may be required 1) to prevent the production of excess retinal cells, or 2) for normal retina formation, independent of proliferation. In Aim 1, morphometric analysis, flow cytometry and EdU labelling will determine where defects are first detected, if and when retinal cell number is altered, and if cycling RPCs are observed with retinal expansion. In Aim 2, we precisely define the temporal and spacial expression pattern to determine which cell types express Maturin, and if that expression is restricted to postmitotic cells. In Aim 3, mice with tamoxifen-inducible null alleles of Maturin will be used to determine precisely when Maturin loss triggers retinal expansion. This work is significant, as Maturin may be required, independent of proliferation, for normal retina development or maintenance. Alternatively, Maturin may control retina size by inhibiting reentry of retinal cells into the cell cycle. This would be an exciting possibility as it would suggest inhibiting Maturin could potentially reactivate retinogenesis in the mammalian eye. Therefore, this project perfectly fits within the NEI's audacious goal to ?Regenerate neurons and neural connections in the eye and visual system.?